World Health Organization regional assessments of the risks of poliovirus outbreaks.

While global polio eradication requires tremendous efforts in countries where wild polioviruses (WPVs) circulate, numerous outbreaks have occurred following WPV importation into previously polio-free countries. Countries that have interrupted endemic WPV transmission should continue to conduct routine risk assessments and implement mitigation activities to maintain their polio-free status as long as wild poliovirus circulates anywhere in the world. This article reviews the methods used by World Health Organization (WHO) regional offices to qualitatively assess risk of WPV outbreaks following an importation. We describe the strengths and weaknesses of various risk assessment approaches, and opportunities to harmonize approaches. These qualitative assessments broadly categorize risk as high, medium, or low using available national information related to susceptibility, the ability to rapidly detect WPV, and other population or program factors that influence transmission, which the regions characterize using polio vaccination coverage, surveillance data, and other indicators (e.g., sanitation), respectively. Data quality and adequacy represent a challenge in all regions. WHO regions differ with respect to the methods, processes, cut-off values, and weighting used, which limits comparisons of risk assessment results among regions. Ongoing evaluation of indicators within regions and further harmonization of methods between regions are needed to effectively plan risk mitigation activities in a setting of finite resources for funding and continued WPV circulation.

Extensive methylation is associated with beta-catenin mutations in hepatocellular carcinoma: evidence for two distinct pathways of human hepatocarcinogenesis.

Hepatocellular carcinoma (HCC) with p53 mutations is usually characterized by extensive chromosomal instability (CIN), whereas those with beta-catenin mutations have relatively less CIN and the molecular pathogenesis of these tumors is unknown. Methylation of CpG dinucleotides in the promoters of cancer-related genes is another characteristic feature of HCCs. The aim of this study was to determine the contribution of the methylator phenotype to HCC and its relationship to genomic instability. Fractional allelic loss (FAL) was determined using 400 microsatellite markers in 81 HCCs and 77 corresponding noncancerous livers as a measure of CIN. Methylation of 21 genetic loci was quantitated using combined bisulfite restriction analysis. Using hierarchical clustering analysis based upon the quantification of methylation levels, all HCCs were segregated into two groups characterized by either limited or extensive methylation. Mutations in the beta-catenin and p53 genes were determined by DNA sequencing. We found that the methylation levels were significantly higher in the HCCs than in noncancerous livers in 18 of the 21 loci (P values ranged from 0.035 to <0.0001). Among 18 loci, elevated levels of methylation at nine loci were significantly associated with beta-catenin mutations (P values ranged from 0.02 to <0.0001). In addition, the presence of beta-catenin mutations was associated with HCCs in the extensive methylation group (P < 0.0001), whereas p53 mutations correlated with high FAL scores (P = 0.0036). These data suggest that HCCs can be classified into two distinct categories based upon promoter methylation, CIN, and mutations of cancer-related genes. HCCs with extensive methylation harbor frequent beta-catenin mutations, whereas HCCs with high levels of CIN are associated with p53 mutations, suggesting the presence of two independent pathways for the pathogenesis of HCC.